Asocainol [(+)-2,12-dimethoxy-1-hydroxy-7-methyl-6-phenethyl-5,6; 8,9-tetrahydro-7H-dibenz(d,f)azonine]-- is a pharmaceutical agent known from DE-PS 30 07 710, which blocks nerve impulses and is particularly suitable for use as a local anesthetic and as an antiarrhythmic. It is therefore particularly suited for surface anesthesia and for the therapy of cardiac dysrhythmia.
The object of the present invention is to improve the synthesis of (+)-asocainol in a way to prevent the occurrence of inactive and undesired side products, or to convert these inactive and undesired side products into useful products.
This object was resolved by the thermal isomerization of a diastereomer of the (+)-asocainol to the (-)-enantiomer of this substance and the formation of the racemate from the two optical antipodes.
By means of x-ray structure analysis an absolute configuration according to Formula I was determined for (+)-asocainol. ##STR1##
Theoretically asocainol may occur in four different isomeric forms caused by:
(1) The asymmetric C-atom in Position 6 PA0 (2) A biphenyl asymmetry in the bond C13a-C13b. PA0 S-configuration with regard to the biphenyl asymmetry, PA0 R-configuration on C6. PA0 (1) Inversion of the (R,R)-isomer to the (S,S)-configuration; PA0 (2) preparation by Grignard synthesis according to DE-PS 30 07 710 using "unnatural" thebaine.
The biphenyl asymmetry is caused by the two phenyl rings not being on one plane but arranged almost vertically to one another. The following configurations are therefore conceivable: EQU (R,R) (S,S) (R,S) (S,R)
The pairs (R,R) and (S,S) and the pairs (R,S) and (S,R) are enantiomers theoretically forming one racemate each. Enantiomers have identical chemical structures. They are alike in all their physical properties with the exception of the sign for the rotation of the polarized light.
Also their chemical behavior towards achiral reagents is alike. With chiral compounds, however, enantiomers react differently which may be useful for separating them from racemic mixtures.
In the case of asocainol there is not only optical "isomerism" but also diastereomerism. The characteristic of diastereomers is that they are hot mirror images of each other.
Thus the pairs (R,R) and (S,S) are diastereomeric to the pairs (S,R) and (R,S). Likewise the racemate (R,S; S,R) is a diastereomer of racemate (S,R; R,S). The configuration first mentioned with the pair always relates to the biphenyl asymmetry, the second to the asymmetric C-atom in Position 6. (S,R) means:
When synthesizing (+)-asocainol according to Example 10 of DE-PS 30 07 710 from natural thebaine (Merck Index 1976 Number 8988) the hydrochloride is produced in a yield of 21% of theory. In addition to the desired (+)-asocainol with the configuration (R,R) there results in an extremely unfavorable weight ratio of 1:3.25 the inactive and therefore useless diastereomer with the configuration (R,S). All previous attempts to shift this unfavorable isomer ratio by changing the synthetic parameters, e.g., with other solvents and varying temperatures, quantity ratios or concentrations, in order to increase the yield of the desired isomer were unsuccessful. Surprisingly it has now been found that the undesirable diastereomer (R,S) to some extent rearranges itself in the biphenyl system when heated above its melting point (138.degree. C.), so that 40% of the (R,S) diastereomers can be converted to the (S,S) enantiomers. Although it was possible to racemize (+)-asocainol, the (S,S)-isomer cannot be converted to (+)-asocainol with (R,R)-configuration. Such conversion is not even in part possible so that at first there was no way to find a meaningful use for the "false" enantiomer of (+)-asocainol. However, pharmacological investigations surprisingly showed that the (S,S)-isomer also possesses antiarrhythmic activity. The synthesis of the racemate (R,R; S,S) from equal parts of (+)-asocainol in (R,R)-form and (S,S)-isomers gave a surprising pharmacologic result. Instead of the additive effect expected a marked synergistic antiarrhythmic effect was found [Arch. Pharmacol. Suppl., 319 (1982) Nr. 145]. This did not only solve the problem of what to do with the unusable (R,S)-isomer but quite surprisingly also improved the effectiveness of the (+)-asocainol according to DE-PS 30 07 710. The solution of the problem according to the invention is thus even more valuable since there was no way known to obtain the (S,S)-enantiomer of the (+)-asocainol.
Theoretically conceivable were the following ways to prepare the (S,S)-isomer;
Both ways proved not to be practicable. So far it has been impossible to produce an inversion and "unnatural" thebaine as the enantiomer of the natural thebaine is not available for a process of any technical use. The "direct" production of the racemate by racemization of (+)-asocainol or by Grignard reaction out of racemic thebaine was equally impossible since racemic thebaine is technically inaccessible and (+)-asocainol cannot be racemized by known means.
Since, as mentioned above, any better activity could not be expected from the racemate (R,R; S,S) as compared with (+)-asocainol no further attempts were made to produce and test the racemate. Only the unexpectedly found possibility to convert the (R,S)-configuration thermally into the (S,S)-configuration led to the discovery of the surprising synergistic effect of the asocainol enantiomers (R,R) and (S,S) combined to the racemate.
The following structural Diagram II shows the four possible configurations and the symbols of their racemates. ##STR2##